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Avastin, Once Considered Promising for Glioblastoma, Disappoints in Large Trial

ARTICLE IN BRIEF

Two new reports found that the monoclonal antibody that targets vascular endothelial growth factor A showed improvement in the duration of progression-free survival — by three to four months — for glioblastoma, but did not impact overall survival.

Results from two large studies testing bevacizumab (Avastin) for newly diagnosed glioblastoma found that the monoclonal antibody that targets vascular endothelial growth factor A (VEGF-A) showed improvement in the duration of progression-free survival — by three to four months — but did not impact overall survival. The results were published in the Feb. 20 issue of The New England Journal of Medicine (NEJM).

Bevacizumab for treatment of recurrent glioblastoma was conditionally approved by the US Food and Drug Administration (FDA) in 2009 after two open-label studies showed a strong signal in patients with recurrent disease. Bevacizumab works by slowing the growth of new blood vessels. In the open-label studies, tumors appeared to shrink on MRI scans in 30 to 45 percent patients on bevacizumab and there was also less steroid use among patients on the monoclonal antibody. The accelerated acceptance still meant that Genentech, developers of the drug, needed a double-blind placebo-controlled study to prove that it relieved symptoms and helped prolong life.

The latest data from the studies, sponsored by Roche and Genentech, will make a formal FDA approval for recurrent disease more difficult, several neuro-oncologists told Neurology Today.

“Of course, we are disappointed,” said Mark R. Gilbert, MD, a professor in the department of neuro-oncology at the University of Texas MD Anderson Cancer Center and principal investigator of the Radiation Therapy Oncology Group (RTOG) 0825 study, one of the NEJM studies. “We do clinical trials to get answers. And finding that a drug might not be all that helpful is very important to know.”

The RTOG 0825 initially enrolled over 900 patients but only 637 adults with newly diagnosed glioblastoma were entered into the multicenter study. The researchers included only patients who were able to have a tumor resection. The National Cancer Institute funded the study and supplied the medication. The researchers also had an unrestricted educational grant by Genentech. The company initially developed the drug and is now in partnership with F. Hoffman La-Roche.

The other study, the Avastin in Glioblastoma (AVAglio) study, was funded by Roche and carried out at 120 sites in 23 countries around the world. They enrolled 921 patients. The design of the study differed somewhat from the RTOG 0825 study. AVAGlio, led by Olivier L. Chinot, MD, of Aix-Marseille University in France, allowed patients who could not have tumor resection, only a diagnostic biopsy, to enter the study. Patients in both studies received either bevacizumab or placebo concurrently with temozolomide and radiotherapy.

The primary endpoints of both studies were also the same: a significant change in progression-free survival and overall survival. The investigators looked at a number of secondary endpoints, including differences in the time to steroid use or a reduction in steroid use, functional status, neurocognitive changes, symptom burden, and quality of life. The secondary endpoints differed between the two studies.

In the analysis of the secondary measures, differences emerged, however, between the two studies; this has sparked a cry for further independent scrutiny, particularly regarding the quality of life measures. The interpretation of the findings could have a hand in an oncologist's decision to offer the medicine to their newly diagnosed patients. Although no controlled, randomized studies have been performed, there is no debate among experts in the field that the medicine has value in patients with recurrent disease.

“Given the limitations of some of these secondary measures, it is hard to know whether the statistical methodologies used created unintentional biases,” said Timothy F. Cloughesy, MD, director of neuro-oncology and professor of neurology at University of California, Los Angeles (UCLA). Dr. Cloughesy was the principal investigator for the US arm of the AVAglio study. “We are all struggling with this right now.”

RTOG 0825 STUDY

Bevacizumab or placebo was administered intravenously, starting at week four of radiotherapy and continuing until disease progression, severe treatment-related toxicity, or completion of adjuvant therapy. A maintenance treatment with temozolomide began a month after the completion of radiotherapy. The treatment was planned for six cycles but the oncologist could extend it to 12 cycles if there were no serious adverse events and evidence of benefit. Once there was evidence that the tumor progressed, the blinded code for that patient was broken. If they were on placebo, they could begin on bevacizumab. They could continue receiving bevacizumab if they had been on the study dose.

The patients had clinical assessments, blood analyses, and brain-imaging scans done throughout the study. They also completed several neurocognitive tests and quality-of-life questionnaires. Progression was defined as an increase in tumor size by at least 25 percent or the development of a new lesion, said Dr. Gilbert. (Due to possible treatment-related changes during radiotherapy, they did not consider tumor progression within the first three months following radiotherapy.)

The study was a collaborative effort between the RTOG, the Cancer Therapy Evaluation Program at the National Cancer Institute, The North Central Cancer Treatment Group, and the Eastern Cooperative Oncology Group. RTOG statisticians did all of the analytical work. The pathological specimens were tested at one central location.

The median overall survival was 15.7 months in the bevacizumab group and 16.1 months in the placebo group. The median duration of progression-free survival was 10.7 months in the bevacizumab group and 7.3 months in the placebo group (p=0.007).

Dr. Gilbert said that they found that patients on bevacizumab showed greater deterioration in neurocognitive functioning than those on placebo, as well as worsening on tests of symptom burden, mood, and activity levels. There were also more serious adverse events, including hypertension (4.2 percent vs. 0.9 percent), thromboembolic disease (7.7 percent vs. 4.7 percent), visceral perforation (1.2 percent vs. 0.4 percent), serious hemorrhage (1.5 percent vs. 0.9 percent), and wound dehiscence (1.5 percent vs. 0.9 percent). Serious neutropenia was more common in the bevacizumab group (10 percent vs. 5.1 percent).

“Some patients on prolonged bevacizumab, despite stable imaging studies, appeared clinically worse but the reason could not be determined,” said Dr. Gilbert. “These studies do not support the use of bevacizumab in newly diagnosed patients.” He added that he continues to use it for recurrent disease. “These patients are much sicker,” he explained. “I find that it does reduce symptom burden and add to the quality of life for these patients.”

The researchers have collected tumor tissue for further testing to see if there was a subpopulation of patients who did better on the drug than others.

AVAGLIO STUDY

In the same issue of the NEJM, Dr. Chinot and colleagues from 120 centers around the world, reported that they too showed no survival benefit but a significant signal for progression free survival, 10.6 versus 6.2 months.

Contrary to the RTOG 0825 study, the AVAglio study found that the bevacizumab group had better maintenance of quality of life and performance status. The monoclonal antibody was also associated with more frequent grade 3 or higher adverse events: 66.8 percent versus 51.3 percent.

This study included patients who had a biopsy (12 percent) but could not undergo resection because of tumor location. The design of the study was otherwise similar. Progression was based on MRI findings, clinical assessment, and steroid use.

Dr. Chinot said they also obtained neurocognitive and quality of life information. They tracked global health status, physical and social functioning, motor dysfunctions, and communication deficits.

Half of the 921 patients enrolled were randomly assigned to the bevacizumab group, and the others to the placebo group. There was no difference in overall survival. They reported that the median progression-free survival was 10.6 months in the bevacizumab group and 6.2 months in the placebo group (p<0.001). Dr. Chinot said that the two studies used different tools to assess progression-free survival.

DIFFERENCES IN QUALITY OF LIFE

It was in the quality-of-life assessments that the two studies began to look very different. (This study did not include formal neurocognitive testing on enough patients to report findings.) According to Dr. Chinot, quality of life was maintained longer in patients in the bevacizumab group compared to those in the placebo group. Patients in the bevacizumab group were also more likely to have discontinued their steroid use during the study, 66.3 percent of the patients receiving bevacizumab as compared with 47.1 percent of the patients receiving placebo. The time to steroid use was also longer with bevacizumab than with placebo (12.3 months vs. 3.7 months).

“We looked at the data very closely to detect a decrease in quality of life,” said Dr. Chinot. “We found that quality-of-life was maintained throughout the study.” He said that the deterioration noted in patients on bevacizumab in the RTOG 0825 study could be due to unrecognized tumor progression, he added.

“I am in favor of an independent review of the data from both studies,” said Dr. Chinot. “It is important for patients.”

WHEN TO USE CLINICALLY

The question comes down to this, both study investigators said: Should oncologists use bevacizumab up front or at recurrence?

“Because there is no advantage for overall survival we can't say this should be standard of care,” Dr. Chinot said. “But we can discuss it as an option for patients.”

UCLA's Dr. Cloughesy added that progression-free survival may be important to patients with tumors that are growing in regions that can impact functional independence. He also agreed that there should be an independent analysis of data from both studies. “We have to figure out why there are differences in the two studies,” he added.

EXPERTS WEIGH IN

Many oncologists who have read both studies agree that there are questions that need addressing. Nimish A. Mohile, MD, assistant professor of neurology and oncology at the University of Rochester Medical Center, said that he “would use it only at recurrence.” But he would consider it if he thought that it impacted on quality of life.

Another vexing issue, said Patrick Wen, MD, director of the Center for Neuro-oncology at Dana Farber-Brigham and Women's Cancer Center in Boston, is that blocking VEGF actually has an effect on newly-forming blood vessels and that could make it harder to get a good contrasting image of the tumor on the MRI scan. It could make scans look better but have nothing to do with the medicine's anti-tumor effect. “Tumors may be progressing earlier but we may not see it in the bevacizumab group,” he said. “The hope is that we can get access to the study data so that we can do an independent analysis and figure out why there are differences in the findings.”

Michael Prados, MD, professor of neurosurgery at University of California-San Francisco, wrote an editorial on the findings from the two NEJM studies, in the April issue of Neuro-oncology. “These are complicated studies to analyze,” said Dr. Prados. “The interpretation of the quality of life, symptom scales, and patient reported outcome measures are complex and difficult to accurately compare across studies; and the cross-over design (patients on placebo can go on to bevacizumab when the tumor grows or a new one develops) makes it hard to know if there was or was not a real survival benefit. This leaves you with some uncertainty about the overall clinical benefit of this agent.”

He added “that the studies left us with many questions that still need to be resolved.”

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